The New England Journal of Medicine December 05, 2002

A Comparison of Rate Control and Rhythm Control in Patients with Recurrent Persistent Atrial Fibrillation

Isabelle C. Van Gelder et al.

Bottom Line

In patients with recurrent persistent atrial fibrillation, a strategy of rate control is non-inferior to rhythm control for the prevention of cardiovascular morbidity and mortality.

Key Findings

1. The primary composite endpoint occurred in 17.2% (44 of 256) of patients in the rate-control group compared to 22.6% (60 of 266) in the rhythm-control group (absolute difference -5.4%).

2. The 90% upper boundary of the absolute difference was 0.4%, which was well within the prespecified non-inferiority margin of 10%, confirming that rate control was not inferior to rhythm control.

3. At a mean follow-up of 2.3 years, only 39% of patients in the rhythm-control group and 10% in the rate-control group were in sinus rhythm.

4. The distribution of the individual components of the primary endpoint (cardiovascular death, heart failure, thromboembolic complications, bleeding, pacemaker implantation, and severe drug adverse effects) was similar between both groups.

Study Design

Design

RCT

Open-Label

Sample

522

Patients

Duration

2.3 yr

Median

Setting

Multicenter, Netherlands

Population Patients with recurrent persistent atrial fibrillation after a previous electrical cardioversion.

Intervention Rate-control strategy (rate-slowing medication targeting a resting heart rate <100 bpm and oral anticoagulants).

Comparator Rhythm-control strategy (serial electrical cardioversions, antiarrhythmic drugs, and oral anticoagulants).

Outcome Composite of death from cardiovascular causes, heart failure, thromboembolic complications, bleeding, implantation of a pacemaker, and severe adverse effects of drugs.

Study Limitations

• The study utilized an open-label design, which could introduce bias regarding subjective outcomes or decisions to hospitalize and intervene.

• The composite endpoint included softer components, such as adverse effects of drugs and pacemaker implantation, which inherently penalize the rhythm-control strategy.

• The relatively short mean follow-up duration of 2.3 years may not capture the long-term clinical consequences or potential benefits of maintaining sinus rhythm.

• The small sample size (N=522) limited the statistical power to detect meaningful differences in hard individual endpoints like cardiovascular mortality or stroke.

• Findings were based on older antiarrhythmic drug regimens; modern rhythm-control interventions, such as catheter ablation, were not evaluated and are known to be more efficacious and better tolerated.

Clinical Significance

The RACE trial, published concurrently with the AFFIRM trial, fundamentally changed the management of atrial fibrillation. It demonstrated that aggressively pursuing sinus rhythm with repeated cardioversions and antiarrhythmic drugs does not yield superior cardiovascular outcomes compared to a simpler, better-tolerated rate-control strategy. This established rate control as a safe and practical first-line therapy for recurrent persistent atrial fibrillation.

Historical Context

Prior to 2002, clinical practice strongly favored rhythm control based on the intuitive premise that restoring normal sinus rhythm would improve hemodynamics, prevent atrial remodeling, and eliminate stroke risk. The simultaneous publication of the RACE and AFFIRM trials in the New England Journal of Medicine triggered a paradigm shift toward rate control. Over time, recent trials (like EAST-AFNET 4 and CABANA) have reinvigorated early rhythm control using safer techniques like catheter ablation, but RACE remains a historic cornerstone study that defined the standard of care for two decades.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the physiological consequences of uncontrolled atrial fibrillation that make rate or rhythm control necessary, and why might attempting to maintain normal sinus rhythm paradoxically increase patient risk?

Key Response

Uncontrolled AF leads to reduced diastolic filling time and loss of atrial kick, causing heart failure and increasing thromboembolic risk. Paradoxically, rhythm control relies on antiarrhythmic drugs which can be proarrhythmic or cause severe systemic toxicity, often offsetting the physiological benefits of sinus rhythm.

Resident

When evaluating a patient with recurrent persistent atrial fibrillation in the clinic, what specific patient characteristics should prompt you to choose a rate control strategy over a rhythm control strategy based on the RACE trial?

Key Response

Rate control is preferred for older, asymptomatic or minimally symptomatic patients, and those with structural heart disease where antiarrhythmics carry high risk. Rhythm control is reserved for highly symptomatic patients, as the trials showed no mortality or morbidity benefit to routine rhythm control.

Fellow

The RACE trial relied heavily on antiarrhythmic drugs and electrical cardioversion for the rhythm control arm. How does the widespread use of catheter ablation for atrial fibrillation alter the applicability of the RACE findings to contemporary electrophysiology?

Key Response

RACE tested a pharmacological rhythm control strategy where drug toxicity negated the benefits of sinus rhythm. Modern ablation offers a non-pharmacological rhythm control strategy with lower long-term systemic toxicity and better efficacy, as suggested by contemporary trials like EAST-AFNET 4 which advocate for early rhythm control.

Attending

Despite trials like RACE demonstrating non-inferiority of rate control, both physicians and patients often have a strong psychological drive to restore normal rhythm. How do you reframe the goals of care for a highly anxious patient who views remaining in AF as a failure?

Key Response

The teaching point is shifting the clinical goal from electrocardiographic normalization to symptom management and stroke prevention. Physicians must explain that aggressive attempts to force sinus rhythm introduce dangerous medication side effects without extending life, making rate control the medically superior choice for asymptomatic patients.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The RACE trial utilized a composite primary endpoint including cardiovascular death, heart failure, thromboembolism, bleeding, pacemaker implantation, and severe adverse drug effects. How does including treatment-specific adverse events in the primary efficacy outcome complicate the statistical assessment of non-inferiority?

Key Response

Including treatment-specific harms directly in the composite efficacy endpoint conflates efficacy with safety. This makes it difficult to disentangle whether rate control is truly non-inferior in preventing disease progression, or if the rhythm control arm simply accumulated excess iatrogenic events, potentially skewing the non-inferiority margin.

Journal Editor

In evaluating the methodological rigor of the RACE trial, what concerns arise from the open-label design and the crossover rate between the treatment arms, and how might these factors bias the primary analysis?

Key Response

An open-label design introduces ascertainment bias for subjective composite components like heart failure or pacemaker indications. Furthermore, patients crossing over from rhythm to rate control dilute the intention-to-treat analysis, inherently biasing the hazard ratios toward the null and making it easier to falsely conclude non-inferiority.

Guideline Committee

Based on the evidence from RACE and AFFIRM, how do current ACC/AHA guidelines grade the recommendation for rate versus rhythm control in asymptomatic patients with recurrent AF, and what specific criteria necessitate a shift to rhythm control?

Key Response

Current ACC/AHA guidelines strongly recommend rate control as the initial strategy for asymptomatic patients (Class I), supported by RACE demonstrating no mortality benefit to rhythm control. A shift to rhythm control is recommended primarily when patients remain unacceptably symptomatic despite adequate rate control or in cases of tachycardia-mediated cardiomyopathy.

Clinical Landscape

Noteworthy Related Trials

2002

AFFIRM Trial

n = 4,060 · NEJM

Tested

Rhythm-control strategy

Population

Patients aged 65 or older with AF and stroke risk factors

Comparator

Rate-control strategy

Endpoint

Overall mortality

Key result: No significant difference in overall mortality was found between rate-control and rhythm-control strategies.

2019

CABANA Trial

n = 2,204 · JAMA

Tested

Catheter ablation

Population

Patients with new-onset or untreated AF requiring therapy

Comparator

Medical therapy (rate or rhythm control)

Endpoint

Composite of death, disabling stroke, serious bleeding, or cardiac arrest

Key result: Catheter ablation did not significantly reduce the primary composite endpoint compared to medical therapy.

2020

EAST-AFNET 4 Trial

n = 2,789 · NEJM

Tested

Early rhythm-control therapy

Population

Patients with early AF (diagnosed within 1 year) and cardiovascular conditions

Comparator

Usual care (predominantly rate control)

Endpoint

Composite of cardiovascular death, stroke, or hospitalization for HF or ACS

Key result: Early rhythm control resulted in a significantly lower risk of adverse cardiovascular outcomes compared to usual care.

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